Role of natural killer cells in hormone-independent rapid tumor formation and spontaneous metastasis of breast cancer cells in vivo

Dewan, Zahidunnabi; Takahashi, Hiroshi; Takada, Masahiro; Tanaka, Yuetsu; Abé, Hiroyuki; Sata, Tetsutaro; Toi, Masakazu; Yamamoto, Naoki

doi:10.1007/s10549-006-9416-4

Cited by 63 publications

(51 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Among invasive BCs, the cases in which NK cell infiltrates still displayed high expression of NCRs, NKG2D, and DNAM-1 receptors, and so which could still be considered as activated cells, have a good prognostic index. NK cells were our primary population of interest considering that invasive tumors preferentially develop in an NK-deficient mouse background (6,7). However, some of the affected receptors, such as DNAM-1, NKG2D, and NKG2A, are also expressed by specific populations of T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Breast tumor cells transplanted into NOD/SCID mice (which lack adaptive immunity) form noninvasive tumors, whereas the same cells transplanted into NOD/SCID/γ-c null mice (no adaptive immunity and no NK cells) form invasive tumors that metastasize rapidly (6). This effect is strictly dependent on NK cells (7). Similarly, in a highly metastatic model, BC metastasized to the lung only after elimination of NK cells by Tregs (8).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity

Mamessier¹,

Sylvain²,

Thibult³

et al. 2011

J. Clin. Invest.

539

494

View full text Add to dashboard Cite

NK cells are a major component of the antitumor immune response and are involved in controlling tumor progression and metastases in animal models. Here, we show that dysfunction of these cells accompanies human breast tumor progression. We characterized human peripheral blood NK (p-NK) cells and malignant mammary tumor-infiltrating NK (Ti-NK) cells from patients with noninvasive and invasive breast cancers. NK cells isolated from the peripheral blood of healthy donors and normal breast tissue were used as controls. With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity. Importantly, Ti-NK cells had more pronounced impairment of their cytotoxic potential than p-NK cells. We also identified several stroma-derived factors, including TGF-β1, involved in tumor-induced reduction of normal NK cell function. Our data therefore show that breast tumor progression involves NK cell dysfunction and that breast tumors model their environment to evade NK cell antitumor immunity. This highlights the importance of developing future therapies able to restore NK cell cytotoxicity to limit/prevent tumor escape from antitumor immunity. IntroductionBreast cancer (BC) is the primary cause of cancer deaths in women. The main cause of this mortality is the metastatic spread to other organs (1). Metastasis occurs when tumor cells acquire invasive features (2) and the ability to escape from antitumor immunity (3, 4). Defects in antitumor immunity may also facilitate BC occurrence. Indeed, mice deficient in IFN-γ production spontaneously develop mammary tumors (5). Breast tumor cells transplanted into NOD/SCID mice (which lack adaptive immunity) form noninvasive tumors, whereas the same cells transplanted into NOD/SCID/γ-c null mice (no adaptive immunity and no NK cells) form invasive tumors that metastasize rapidly (6). This effect is strictly dependent on NK cells (7). Similarly, in a highly metastatic model, BC metastasized to the lung only after elimination of NK cells by Tregs (8).Advanced BC patients show defects in antitumor immunity, such as alterations of DC maturation (9) and an increase in Treg infiltrates (10). Major impairment of peripheral blood NK cell maturation and cytotoxic functions has also been reported in metastatic BC (11). Several gene expression profiling studies have shown that a better outcome is associated with a strong cytotoxic infiltrate containing NK cells (12)(13)(14)(15). These data suggest that BC progression is linked to antitumor immunity efficiency and particularly to NK cells. However, the precise relationships between NK cells and BC progression in humans have not been studied so far.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity

Mamessier¹,

Sylvain²,

Thibult³

et al. 2011

J. Clin. Invest.

539

494

View full text Add to dashboard Cite

show abstract

“…In human papillomavirus (HPV)-related tumors, such as cervix carcinoma and high-grade squamous intraepithelial lesions, loss of NCR expression on NK cells correlated with their weak cytotoxicity, HPV-16 infection, and advanced clinical stage (31). Even in breast cancers that are prone to be controlled by NK cells (32) and contain NK TILs enriched in CD56 bright cells, NK TILs exhibited low expression of NCR and defective functions [antibody-dependent cell-mediated cytotoxicity (ADCC), cytokine release, and degranulation] that inversely correlated with the Nottingham prognostic index and upregulated NKG2A inhibitory receptors (33). In contrast, in kidney cancers, high NK TIL content was associated with high CD16 expression on NK cells but low cytotoxic function after ex vivo reactivation using interleukin (IL)-2 or NKp46 stimulation (34).…”

Section: Discussionmentioning

confidence: 99%

Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

et al. 2013

View full text Add to dashboard Cite

Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8þ T cells with a T-helper cell 1(T H 1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes (TIL) expressing CD3, Foxp3, or NKp46 (NCR1) in a cohort of patients with localized GIST. We found that CD3 þ TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class I MHC expression despite imatinib mesylate treatment. High densities of CD3 þ TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokinesecreting CD56 bright (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK infiltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratification of patients with GIST. Cancer Res; 73(12); 3499-510. Ó2013 AACR.

show abstract

“…As innate immune effectors, NK cells are one of the major infiltrating immune cells in breast cancer and are endowed with the capability of recognizing nascent transformed cells to prevent tumorigenesis and subsequent metastasis (12)(13)(14)(15). Breast cancer stem-like cells (BCSC) are resistant to therapies and are highly metastatic (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells

et al. 2014

View full text Add to dashboard Cite

Breast cancer stem-like cells (BCSC) are crucial for metastasis but the underlying mechanisms remain elusive. Here, we report that tumor-infiltrating natural killer (NK) cells failed to limit metastasis and were not associated with improved therapeutic outcome of BCSC-rich breast cancer. Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis. The breast cancer cell differentiation-inducing agent, all-trans retinoic acid, restored the miR20a-MICA/MICB axis and sensitized BCSC to NK cell-mediated killing, thereby reducing immune escape-associated BCSC metastasis. Together, our findings reveal a novel mechanism for immune escape of human BCSC and identify the miR20a-MICA/MICB signaling axis as a therapeutic target to limit metastatic breast cancer. Cancer Res; 74(20); 5746-57. Ó2014 AACR.

show abstract

Role of natural killer cells in hormone-independent rapid tumor formation and spontaneous metastasis of breast cancer cells in vivo

Cited by 63 publications

References 36 publications

Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity

Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity

Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells

Contact Info

Product

Resources

About